Recent studies with a mouse model indicate that alpha-tocopherol (vitamin E) inhibits the induction of skin tumors by ultraviolet light (UV-B). Topical vitamin E is an attractive agent for the chemoprevention of skin cancer, since it is nontoxic, is easily incorporated into skin care products, and exhibits UV absorption characteristics similar to those of commercial sunscreening agents. Alpha-Tocopherol, an essential dietary nutrient, protects tissues against oxidative damage caused by free radicals and other oxidants. UV-B initiates free radical reactions in the epidermis and also causes photochemical reactions that damage DNA. However, repeated or sustained UV-B exposure may deplete epidermal stores of diet-derived alpha-tocopherol and cause oxidative damage and DNA photodamage. The overall goal of this project is to determine how alpha-tocopherol prevents the induction of skin cancer by UV-B. This project will test the hypothesis that topically applied alpha-tocopherol supplements and enhances endogenous epidermal antioxidant defenses and that this action prevents precarcinogenic oxidative damage and photodamage caused by UV- B. This project will test this hypothesis in the mouse model by investigating the effects of UV-B on the epidermal metabolism of alpha- tocopherol and the ability of alpha-tocopherol and its derivatives to suppress both oxidative damage and DNA photodamage. First, the effect of single or repeated UV-B exposures on rates of epidermal alpha- tocopherol metabolism will be studied with the aid of stable isotope labeled alpha-tocopherols and gas chromatography-mass spectrometry analysis. Next, sensitive analytical methods will be used to measure the inhibition by topically applied alpha-tocopherol of photochemical damage to epidermal DNA and of oxidative damage to epidermal lipid and DNA. The metabolism and antioxidant actions of topically applied and diet-derived alpha-tocopherol will then be measured separately and simultaneously in UV-B exposed mouse skin. Finally, the hydrolysis of alpha-tocopherol esters to free alpha-tocopherol in mouse epidermis will be studied to determine whether the ester forms most commonly used in product formulation effectively supply the active antioxidant form of vitamin E to the epidermis. This study will contribute to human cancer prevention by providing detailed biochemical information about the metabolism and mechanism of action of alpha-tocopherol, an effective chemopreventive agent. This information will provide a much needed mechanistic framework for rationally selecting and evaluating agents for preventing human skin cancer.
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